The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

Abstract

The spindle assembly checkpoint (SAC) is essential for proper sister chromatid segregation. Defects in this checkpoint can lead to chromosome missegregation and aneuploidy. An increasing body of evidence suggests that aneuploidy can play a causal role in tumorigenesis. However, mutant mice that are prone to aneuploidy have only mild tumor phenotypes, suggesting that there are limiting factors in the aneuploidy-induced tumorigenesis. Here we provide evidence that p53 is such a limiting factor. We show that aneuploidy activates p53 and that loss of p53 drastically accelerates tumor development in two independent aneuploidy models. The p53 activation depends on the ataxia-telangiectasia mutated (ATM) gene product and increased levels of reactive oxygen species. Thus, the ATM-p53 pathway safeguards not only DNA damage but also aneuploidy.

Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability

“…28 Interestingly, casp2 À / À mice do not develop spontaneous tumours with age and we do not observe increased thymoma development following repeated low dose IR treatment of mice (unpublished data). This suggests that there may be other limiting factors in aneuploidy-induced tumourigenesis 29 and the function of caspase-2 as a tumour suppressor may become important only following oncogenic stress. Although caspase-2-deficient MEFs display reduced telomere length and reduced p53 activation following DNA damage, we do not detect a complete loss of p53 function.…”

“…27 GIN precedes cellular transformation and oncogenesis and is frequently associated with loss of p53 function. 28,29 The activation of the DDR is therefore critical to maintain genome stability, but the mechanisms underlying the decision to activate DNA repair and survive or to die are not fully understood.…”

Tumor suppressor roles of CENP-E and Nsl1 inDrosophilaepithelial tissues

“…10 Since aneuploidy can be detrimental for cells, additional mutations might contribute to the survival of these cells and to CIN-induced tumorigenesis. Indeed, CIN leads to p53-dependent apoptosis of mammalian cells, 11,12 and mutations in the p53 tumor suppressor gene increase the frequency of spontaneous tumorigenesis observed in CIN mouse models. 11 In Drosophila epithelial tissues, CIN leads to Drosophila p53 (dp53)-independent apoptosis and maintenance of aneuploid cells in the tissue through additional blockade of PCD causes tissue overgrowth, basement membrane (BM) degradation, and host invasiveness.…”

“…Indeed, CIN leads to p53-dependent apoptosis of mammalian cells, 11,12 and mutations in the p53 tumor suppressor gene increase the frequency of spontaneous tumorigenesis observed in CIN mouse models. 11 In Drosophila epithelial tissues, CIN leads to Drosophila p53 (dp53)-independent apoptosis and maintenance of aneuploid cells in the tissue through additional blockade of PCD causes tissue overgrowth, basement membrane (BM) degradation, and host invasiveness. 10 The tumorigenic response of the tissue relies on aneuploid cells delaminating from the epithelium and activating a JNKdependent transcriptional program that triggers the expression of the Matrix Metaloproteinase 1 (MMP1) and the mitogenic molecule Wingless (Wg).…”

Mitosis as an anti-cancer target

“…The presence of extra chromosomes can trigger the activation of stress pathways, owing to protein imbalances, proteotoxic stress and presumably higher levels of reactive oxygen species (Torres et al, 2007;Williams et al, 2008;Li et al, 2010;. Because of activation of these stress pathways, aneuploidy will lead to a decrease in the speed of cell growth and enhanced lethality in an otherwise healthy population of cells (Torres et al, 2007;Williams et al, 2008).…”